TY - JOUR
T1 - Total syntheses of the thiopeptides smythiamicin C and D
AU - Ammer, Carolin
AU - Bach, Thorsten
PY - 2010/12/17
Y1 - 2010/12/17
N2 - The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross-coupling reaction, and two Negishi cross-coupling reactions as key transformations. The central 2,3,6-trisubstituted pyridine ring of the target compounds was introduced as a 2,6-dibromo-3-iodopyridine, which was selectively metalated at the 3-position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross-coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross-coupling at C-6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross-coupling at C-2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross-coupling reactions. The pivotal step involved the diastereoselective addition of 4-bromothiazole-2- magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross-coupling at C-6, amide bond formation, and cross-coupling at C-2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross-coupling at C-2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross-coupling at C-6 with 2-zincated methyl thiazole-5-carboxylate. Cross-coupling reactions paved the way to two short syntheses of amythiamicin C (1) and D (2; see scheme). In the former synthesis, the sequence A-C-B was followed to give access to the title compound 1. In the latter synthesis, the sequence C-B-A was probed and led successfully to amythiamicin D (2) in an extremely short, but less selective, synthetic sequence.
AB - The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross-coupling reaction, and two Negishi cross-coupling reactions as key transformations. The central 2,3,6-trisubstituted pyridine ring of the target compounds was introduced as a 2,6-dibromo-3-iodopyridine, which was selectively metalated at the 3-position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross-coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross-coupling at C-6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross-coupling at C-2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross-coupling reactions. The pivotal step involved the diastereoselective addition of 4-bromothiazole-2- magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross-coupling at C-6, amide bond formation, and cross-coupling at C-2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross-coupling at C-2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross-coupling at C-6 with 2-zincated methyl thiazole-5-carboxylate. Cross-coupling reactions paved the way to two short syntheses of amythiamicin C (1) and D (2; see scheme). In the former synthesis, the sequence A-C-B was followed to give access to the title compound 1. In the latter synthesis, the sequence C-B-A was probed and led successfully to amythiamicin D (2) in an extremely short, but less selective, synthetic sequence.
KW - antibiotics
KW - cross-coupling
KW - macrocycles
KW - natural products
KW - total synthesis
UR - http://www.scopus.com/inward/record.url?scp=78650292242&partnerID=8YFLogxK
U2 - 10.1002/chem.201002144
DO - 10.1002/chem.201002144
M3 - Article
C2 - 20960446
AN - SCOPUS:78650292242
SN - 0947-6539
VL - 16
SP - 14083
EP - 14093
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 47
ER -